生物谷报道：骨髓干细胞趋化到肿瘤生长点后，常常会把自己伪装得和周围癌细胞一样。佛罗里达大学的研究人员在八月版《Stem cells》杂志上发表的文章报道了该现象。但是尚不清楚这些干细胞是否会像有些科学家怀疑的那样，提升肿瘤生长和扩散的能力。出现在该杂志本月网络版上的这项发现其实是对日趋流行的骨髓干细胞癌种子理论的挑战。因为这些细胞只是看起来像癌细胞，其实并无癌细胞的生物学行为。
研究作者Chris Cogle博士是佛罗里达大学干细胞生物学医学工程和再生医学的医学副教授。他说：“它们拥有同样的表面蛋白，就像是套着个相同的外壳。下一个问题是”它们的内脏也是一样的吗？”” Cogle还附属于佛罗里达大学Shands癌症中心，他说：“我们的结果显示这些细胞的行为如同发育拟态；它们进来后就变得看起来很像周围的肿瘤组织，但是它们真的不是肿瘤的种子。最糟糕的是这些细胞能通过分泌生长因子或一些能促进肿瘤生长和存活的蛋白来支撑肿瘤组织。”
研究人员已经炮制出“生长拟态”这个词来形容该现象。这种现象将可能对科学家们在实验室里用来测试抗癌新药的细胞系的完整性产生影响。包含骨髓来源细胞的癌组织中有多达5%的细胞只是看起来像周围的癌。所以当实验用作检测新药效果的恶性组织在实验室里生长时，我们就有可能等到混淆结果，Cogle说道。如果药物有效，那它可能只是作用于那些产生了拟态的骨髓细胞，而不是真正的肿瘤细胞。“如果某癌组织中有骨髓细胞，那么事实上这些细胞可能干扰了我们的癌症研究，而且还可能会改变我们对被研究药物是否有效的判断。”他说，“这个意义就在于部分解释了为什么新的治疗在培养瓶里有效而转到临床就不行了。骨髓污染是其中的一个原因。”
佛罗里达大学的研究人员正在和多所大学和医学中心的科学家们联手，研究具有癌细胞外观的骨髓细胞能否在动物体内长长出肿瘤，以及它们是否具有肿瘤细胞的内部遗传缺陷。Mariusz Ratajczak博士是某大学干细胞发育生物学计划主任兼某杂志编委委员。他说，之所以一些行骨髓移植的患者术后又得了第二次肿瘤，可能是由于准备手术所需的高剂量放疗和化疗造成的。
“源自骨髓的移植细胞包含了一部分干细胞，它们一方面做好事，帮助再生，而另一方面，一旦哪里出了差错，这些细胞也会帮助癌肿的生长，当然这样的几率很少，”Ratajczak说。“这个研究很好的说明了这种可能性是存在的，实际上也阐述了一种新兴的机制。不管怎样，我们知道这些细胞是促进了肿瘤的生长的。他们不是始作俑者，但是却以一些方式通过发育拟态促进了二次肿瘤。”
原文出处：
Stem Cells May Look Malignant, Not Act It
Newswise — Call it the cellular equivalent of big glasses, a funny nose and a fake mustache.
Bone marrow stem cells attracted to the site of a cancerous growth frequently take on the outward appearance of the malignant cells around them, University of Florida researchers report in a paper to be published in the August issue of Stem Cells.
But whether that enables them to fuel cancer’s ability to develop and then spread, as some scientists suspect, is not entirely clear. The findings, available early in this month’s online edition of the journal, actually contest the increasingly popular theory that bone marrow stem cells seed cancer. Instead, these cells might simply look like cancer, not act like it.
“They have the same kind of surface proteins,” said study author Chris Cogle, M.D., an assistant professor of medicine at the UF’s College of Medicine Program in Stem Cell Biology and Regenerative Medicine. “They have the same skin. The next question is ‘Do they have the same guts?’
“Our results indicate these cells act as developmental mimics; they come in and look like the surrounding neoplastic tissue, but they aren’t actually the seed of cancer,” said Cogle, who also is affiliated with the UF Shands Cancer Center. “At the worst, these cells could help support cancerous tissue by providing it with growth factors or proteins that help the cancer grow and survive. At the very least, these marrow cells are just being tricked into coming into the cancerous environment and then made to walk and talk like they don’t usually do.”
The researchers have coined the term “developmental mimicry” to describe the phenomenon, which could have implications for the integrity of the cell lines scientists use to test new cancer drugs in the lab.
Up to 5 percent of cancerous tissue contains marrow-derived cells that look just like surrounding cancer. So when malignant tissue is grown in the laboratory for experiments that test the effects of new drugs, it’s possible the results are muddied, Cogle said. Drugs, if effective, may be targeting the marrow cell mimics, not actual cancer cells.
“If there are bone marrow cells in this cancerous tissue, these cells may actually contaminate our cancer studies and could make a difference as to whether or not investigational drugs we’re testing work or don’t work,” he said. “The significance of this is new treatments may work in the culture dish but may not translate to the clinic or the hospital room, and for many reasons. One of the reasons could be bone marrow contamination.”
In their study, UF researchers evaluated two women who underwent bone marrow transplantation and subsequently developed colonic adenomas, four women who developed skin cancer and one who developed lung cancer.
“We questioned where the cancer was coming from — was it really from the patient or could it have been from the donor bone marrow that we transplanted in the patient?” Cogle said.
Each patient received infusions of bone marrow cells from a brother or an unrelated male donor. That enabled physicians to track the transplanted cells by screening for the Y male chromosome
They found that the cancers were mostly of female origin, but the malignant tissue often contained small areas of male marrow cells.
“This led us to question the extent the donor marrow was participating in these cancers,” Cogle said. “A tumor consists of a mixed bag of cells, not just one solid same-celled block of tissue. What we’re trying to study is the role of these marrow-derived cells within the neighborhood of cancer.”
The researchers then studied mice who underwent bone marrow transplant and developed the same cancers as the women. When they viewed the cancerous tissues under the microscope, they found marrow cells shared outward features of the cancer cells.
Cogle said research conducted elsewhere suggests marrow cells flock to a cancerous site to help set up a blood vessel-friendly environment that feeds the tumor. The current findings, supported by grants from the National Institutes of Health and the James & Esther King Biomedical Research Program, might be an aftereffect of this supporting role, he said.
UF researchers — who collaborated with scientists from Beth Israel Medical Center at New York’s Albert Einstein College of Medicine, Yale University School of Medicine, St. Francis Hospital in Indianapolis and the Penn State Milton S. Hershey Medical Center — are now analyzing whether marrow cells that look like cancer are able to spawn tumors in animals, and whether they harbor the characteristic internal genetic defects of tumor cells.
Some patients who undergo bone marrow transplant later develop secondary cancers because of the high doses of radiation and chemotherapy they receive to prepare them for the procedure, said Mariusz Ratajczak, M.D., Ph.D., director of the Stem Cell Developmental Biology Program at the University of Louisville James Graham Brown Cancer Center and a member of the journal’s editorial board.
“Transplanted cells which are derived initially from the bone marrow can include a population of stem cells which can on one hand do nice things and contribute to regeneration, and on the other hand if something goes wrong, these cells can also contribute to cancer development, of course in very rare cases,” Ratajczak said. “This study has very nicely shown that that possibility exists, and it actually describes a new, novel mechanism. Somehow we know these cells contribute to growing tumor. They may not initiate it but they somehow contribute by developmental mimicry to these secondary malignancies.”
作者简介：
Mariusz Z. Ratajczak
Name: Mariusz Z. Ratajczak
Position: Director of Stem Cell Biology Program at James Graham Brown Cancer Center, University of Louisville
Department: Department of Medicine
Institution: University of Louisville, Louisville, Kentucky, USA
Fields of interest:
· The role of SDF-1-CXCR4 axis in tissue/organ regeneration and cancer metastasis.
· The biology of bone marrow-derived CXCR4 positive embryonic-ljke pluripotent/tissue specific stem cells.
· The role of complement proteins in homing, engraftment and mobilization of hematopoietic stem cells. Autocrine/paracrine regulation of human hematopoiesis.
· The role of HIV-autoprotective chemokines in resistance of human stem cells to HIV.
Recent publications (selected):
M. Kucia, R. Reca, V.R. Jala, B. Dawn, J. Ratajczak, M.Z. Ratajczak:
Bone marrow as a home of heterogenous populations of nonhematopoietic stem cells,
Leukemia , Vol. 19, 2005, pp. 1118-1127.
M. Kucia, R. Reca, K. Miekus, J. Wanzeck, W. Wojakowski,
A. Janowska-Wieczorek, J. Ratajczak, M.Z. Ratajczak:
Trafficking of Normal Stem Cells and Metastasis of Cancer Stem Cells. Involve Similar Mechanisms: Pivotal Role of the SDF-1?CXCR4 Axis,
Stem Cells, Vol. 23, 2005, pp. 879-894.
M. Kucia, J. Ratajczak, M.Z. Ratajczak:
Are Bone marrow stem cells plastic or heterogenous - that is the question,
Exp. Hematol., Vol. 33, 2005, pp. 613-623.
M. Kucia, D. Dawn, G. Hunt, Y. Guo, M. Wysoczynski, M. Majka, J. Ratajczak,
F. Rezzoug, S.T. Ildstad, R. Bolli, M.Z. Ratajczak:
Cells expressing markers of cardiac tissue-committed stem cells reside in the bone marrow and are mobilized into peripheral blood following myocardial infraction,
Cir. Research, Vol. 95, 2004, pp. 1191-1199.
W. Wojakowski, M. Tendera, A. Michalowska, M. Majka, M. Kucia,
K. Maslankiewicz, R. Wyderka, A. Ochala, M.Z. Ratajczak:
The mobilization od CD34+/CXCR4+, CD34+/CD117+, c-Met+ stem cells and mononuclear cells expressing early cardiac, muscle and endothelial markers into peripheral blood in patients with acute myocardial infarction,
Circulation, Vol. 110, 2004, pp. 3213-3220.
M. Wysoczynski, R. Reca, J. Ratajczak, M. Kucia, N. Shirvaikar,
M. Mills, J. Wanzeck, M. Honczarenko, A. Janowska-Wieczorek,
M.Z. Ratajczak:
Incorporation of CXCR4 into Membrane Lipid Rafts Primes Homing-related responses of Hematopoietic Stem Cells to an SDF-1 Gradient,
Blood, Vol. 105, 2005, pp. 40-48.
M.Z. Ratajczak, R. Reca, M. Wysoczynski, M. Kucia, J.T. Baran,
D.J. Allendorf, J. Ratajczak, G.D.Ross:
Transplantation studies in C3-deficient animals reveal a novel role of the third complement component (C3) in engraftment of bone marrow cells,
Leukemia, Vol. 18, 2004, pp. 1482-1490.
J. Ratajczak, R. Reca, M. Kucia, M. Majka, D.J. Allendorf, J.T. Baran,
A. Janowska-Wieczorek, R.A. Wetsel, G.D. Ross, M.Z. Ratajczak:
Mobilization Studies in Mice Deficient in Either C3 or C3a-Receptor (C3aR) Reveal a Novel Role For Complement in Retention of Hematopoietic, Stem/Progenitor Cells in Bone Marrow.
Blood, Vol. 103, 2004, pp. 2071-2078.
M.Z. Ratajczak, M. Kucia, R. Reca, M. Majka, A. Janowska-Wieczorek,
J. Ratajczak:
Stem cell plasticity revisited: CXCR4-positive cells expressing mRNA for early muscle, liver and neural cells "hide out" in the bone marrow,
Leukemia, Vol. 18, 2004, pp. 29-40.
K. Jankowski, M. Kucia, M. Wysoczynski, R. Reca, D. Zhao, E. Trzyna,
M. Zembala, J. Ratajczak, P. Houghton, A. Janowska-Wieczorek,
M.Z. Ratajczak:
Both HGF and SDF-1 Regulate the Metastatic Behavior of Human Rhabdomyosarcoma Cells, but only HGF Enhances their Resistance to Radio-chemotherapy,
Cancer Res., Vol. 63, 2003, pp. 7926-7935.
R. Reca, D. Mastellos, M. Majka, L. Marquez, J. Ratajczak, S. Franchini,
A. Glodek, M. Honczarenko, L.A. Spruce, A. Janowska-Wieczorek,
J.D. Lambris, M.Z. Ratajczak:
Functional receptor for C3a anaphylatoxin is expressed by normal hematopoietic stem/progenitor cells and C3a enhances homing-related responses of early hematopoietic cells to SDF-1,
Blood, Vol. 101, 2003, pp. 3784-3793.
T. Rozmyslowicz, M. Majka, J. Kijowski, S.L. Murphy, D. O'Connover,
M. Poncz, J. Ratajczak, G.N. Gaulton, M.Z.Ratajczak:
Platelet- and megakaryocyte-derived microparticles transfer CXCR4 receptor to CXCR4-null cells and make them susceptible to infection by X4-HIV,
AIDS, Vol. 17, 2003, pp. 33-42.
J. Libura, J. Drukala, M. Majka, O. Tomeascu, J.M. Navenot, M. Kucia,
L. Marquez, S.C. Peiper, F.G. Barr, A. Janowska-Wieczorek, M.Z. Ratajczak:
CXCR4-SDF-1 signaling is active in rhabdomyosarcoma cells and regulates locomotion, chemotaxis and adhesion.
Blood, Vol. 100, 2002, pp. 2597-2606.
A. Janowska-Wieczorek, M. Majka, J. Kijowski, M. Baj-Krzyworzeka,
R. Reca, A.R. Turner, J. Ratajczak, M.A. Kowalska, M.Z.Ratajczak:
Platelet-derived microparticles (PMPs) bind to hematopoietic stem/progenitor cells (HSPC) and enhance their engraftment,
Blood, Vol. 98, 2001, pp. 3143-3149.
M. Majka, A. Janowska-Wieczorek, J. Ratajczak, K. Ehrenman,
M.A. Kowalska, A.M. Gewirtz, S.G. Emerson, M.Z. Ratajczak:
Numerous growth factors, cytokines and chemokines are secreted by human CD34+ cells, myeloblasts, erythroblasts and megakaryoblasts and regulate normal hematopoiesis in an autocrine/paracrine manner,
Blood, Vol. 97, 2001, pp. 3075-3085.
M. Majka, A. Janowska-Wieczorek, J. Ratajczak, M.A. Kowalska, G. Vilaire,
Z.K. Pan, M. Honczarenko, L.A. Marquez, M. Poncz, M.Z. Ratajczak:
Stromal Derived Factor-1 and Thrombopoietin Regulate Distinct Aspects of Human Megakaryopoiesis,
Blood, Vol. 96, 2000, pp. 4142-4151.
M. Majka, T. Rozmyslowicz, B. Lee, Z. Pietrzkowski, G.N. Gaulton,
L. Silberstein, M.Z. Ratajczak:
Bone Marrow CD34+ cells and megakaryoblasts secrete beta-chemokines; implications for infectability by M-tropic human immunodeficiency virus (R5 HIV),
J. Clin. Invest., Vol. 104, 1999, pp. 1739-1749.
B. Lee, J. Ratajczak, R.W. Doms, A.M. Gewirtz, M.Z. Ratajczak:
Coreceptor/chemokine receptor expression on human hematopoietic cells: Biological implications for HIV-1 infection.
Blood, Vol. 93, 1999, 1145-1156.
